tbuckley/cabot-search huggingface dataset:
Abstract 263: PIM kinase regulates actin dynamics in hypoxia
Authors: Corbin C. Jensen, Noel A. Warfel
Journal: Cancer Research (2022)

Abstract One of the leading factors in prostate cancer mortality is the onset of metastatic events. This is seen by the drastic decline in survival rates following tumor escape from the primary site. A key promoter of metastasis is tumor hypoxia, or low oxygen concentration. Our lab previously demonstrated that Proviral Integration site for Moloney murine leukemia virus (PIM)-1, a serine-threonine kinase, is upregulated in hypoxia and that inhibition of PIM1 reduced metastatic occurrence in orthotopic mouse models. Here, we identify a novel signaling pathway that links hypoxia and PIM kinase to the actin cytoskeleton and cell motility. An unbiased screen to discover new PIM substrates in hypoxia identified Abl-Interactor 2 (Abi2), an integral member of the actin regulating Wave Regulatory Complex (WRC), as a novel PIM kinase substrate. Biochemical analysis demonstrates that phosphorylation of Abi2 at our identified PIM sites increases Abi2 stability. Overexpression of PIM1 increases Abi2 and other WRC members at the protein level, resulting in increased actin protrusions and cell motility. CRISPR-generated Abi2 knockout cell lines showed diminished protrusive activity and negated both the necessity and sufficiency of PIM kinase to increases protrusive activity in cancer cells. Lastly, in vivo experiments show that overexpression of PIM1 increases tumor invasion into the surrounding tissue in an Abi2-dependent manner, and small molecule PIM inhibitors significantly reduce invasion. In summary, we uncovered a novel role for PIM1 in promoting cellular motility and protrusion, identified novel phosphorylation sites that control the stability of Abi2 in normoxic and hypoxic conditions, and highlight a novel PIM1/Abi2 signaling axis that regulates hypoxia-induced tumor invasion. This research provides important insight in the role of PIM signaling in prostate tumors and yields preclinical evidence for further use of PIM kinase inhibitors as a means to inhibit tumor invasion, a key driving step in the formation of lethal prostate cancer metastasis. Citation Format: Corbin C. Jensen, Noel A. Warfel. PIM kinase regulates actin dynamics in hypoxia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 263.
Abstract 1743: Identification of mesothelin binding peptide for targeted therapy against pancreatic cancer
Authors: Min-Sung Park, Byungheon Lee
Journal: Cancer Research (2022)

Abstract Pancreatic cancer is the main cause of cancer-related deaths worldwide and is difficult to diagnose before the extensive local invasion and distant organ metastasis. Mesothelin is abnormally overexpressed in tumors such as ovary cancer and pancreatic cancer. Studies show a significant link between mesothelin overexpression and short survival in patients with pancreatic cancer. In this study, we screened a phage displayed-peptide library for peptides that selectively bind to mesothelin using mesothelin-overexpressing cells. After five rounds of screening, we selected a 9-mer peptide (named MSLN-Pep) that preferentially bound to mesothelin-high pancreatic cancer cells such as ASPC-1 and Panc-1 cells over mesothelin-low cells such as HEK 293 cells. MSLN-Pep was efficiently internalized into ASPC-1 cells and inhibited the cell migration and invasion while little affected the phosphorylation of Akt. Moreover, a MSLN-Pep-guided proapoptotic peptide (MSLN-Pep-KLA) exerted selective cytotoxicity against pancreatic cancer cells over mesothelin-low cells. MSLN-Pep-KLA when combined with gemcitabine, a chemotherapeutic agent against pancreatic cancer, sensitized ASPC-1 cells to the gemcitabine treatment. These results suggest that MSLN-Pep is a promising tool for a targeted therapy against pancreatic cancer expressing mesothelin at high levels. Citation Format: Min-Sung Park, Byungheon Lee. Identification of mesothelin binding peptide for targeted therapy against pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1743.
Abstract 617: MEK inhibitor rescued the efficacy of PD-1 blocker in STK11/LKB1 mutated colorectal cancer model
Authors: Demi X. Liu, Jun Zhou, Chenpan Nie, Annie X. An, Henry Q.X. Li, Jingjing Wang
Journal: Cancer Research (2022)

Abstract Introduction: The mechanism of action of primary resistance to PD-1 blockade is largely unknown, however STK11/LKB1 alterations have been reported to have a significant role in primary resistance to PD-1/PD-L1 axis inhibitors in KRAS-mutant lung adenocarcinoma. It is importsnt to identify treatments which can rescue the efficacy of PD-1 blocker in STK11/LKB1-mutant patients. We have developed a STK11 knockout (KO) model using the CT26 colorectal cancer syngeneic line which harbors a KRAS mutation and evaluated the response to checkpoint inhibitor alone and in combination with MEK inhibitors. Method: CT26-STK11KOwas developed by CRISPR/Cas9 technology and STK11/LTB1 deletion was verified by Western Blot. To test the response of the cell line to anti-PD-1 treatment (10mg/kg), we engrafted CT26-WT and CT26-STK11KO tumor lines into BALB/c mice. Tumor growth inhibition (TGI) was assessed as TGI%=(1-Ti/Vi) x100%; Ti as the mean tumor volume of the treatment group on the measurement day; Vi as the mean tumor volume of control group at the measurement day. At termination FACS analysis of different major types of immune cells was performed. Combination with MEK inhibitors, including Trametinib (1mg/kg) was also evaluated. Results: In comparison to CT26-WT tumor growth, PD-1 blocker could not inhibit CT26-STK11KO tumor progression. However, Combinational treatment of Trametinib and anti-PD-1 antibody delayed CT26-STK11KO tumor growth. In CT26-WT tumor bearing mice, anti-PD-1 monotherapy increased total CD45+ immune cells, suggesting an ongoing immune response; significantly increased the ratio between M1 and M2, which might be an indicator for enhanced type I T cell response. CD8+ T cell infiltration in CT26-STK11KO tumors was dramatically decreased associated with increased percentage of G-MDSC which may have contributed to the loss of response to anti-PD-1 treatment. MET inhibitor, Trametinib, decreased G-MDSC and restored CD8+ T cell infiltration and PD-1 blocker efficacy in CT26-STK11KO tumor. Conclusions: We successfully generated a CT26-STK11KO cell line which was valuable for evaluation of PD-1 blocker and MEK inhibitor in STK11/LTB1 deficient tumor, in which Trametinib could rescue the efficacy of PD-1 treatment in CT26-STK11KO tumor via inhibiting G-MDSC. Taken together, our data suggest that altered immune cell infiltration, particularly increased G-MDSCs, in tumor microenvironment might be the reason for poor PD-1 blocker efficacy in CT26-STK11KO tumor. Citation Format: Demi X. Liu, Jun Zhou, Chenpan Nie, Annie X. An, Henry Q.X. Li, Jingjing Wang. MEK inhibitor rescued the efficacy of PD-1 blocker in STK11/LKB1 mutated colorectal cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 617.
Abstract 4233: Generation of a <i>Bicycle</i> NK-TICA™, a novel NK cell engaging molecule designed to induce targeted tumor cytotoxicity
Authors: Fay J. Dufort, Christopher J. Leitheiser, Gemma Mudd, Julia Kristensson, Alexandra Rezvaya, Katie Gaynor, Sandra Uhlenbroich, Liudvikas Urbonas, Heather Scott, Liuhong Chen, Helen Harrison, Michael Skynner, Kevin McDonnell, Philip E. Brandish, Nicholas Keen
Journal: Cancer Research (2022)

Abstract The tumor specific activation of natural killer (NK) cells is an area of active investigation in immune oncology, but to date has relied on complex biologic modalities (e.g., antibodies, fusion proteins, or cell therapies). NK cells are highly responsive immune cells that can detect and eliminate tumor cells and bridge innate to adaptive immune responses. Bicycles® are small (ca.1.5kDa), chemically synthetic, structurally constrained peptides discovered via phage display and optimized using structure-driven design and medicinal chemistry approaches. We have applied the Bicycle platform technology to identify Bicycles® that bind specifically to the key activating receptor, NKp46. When chemically coupled to tumor antigen binding Bicycles, this results in highly potent, antigen-dependent receptor activation and NK cell activation. We term this new class of fully synthetic molecules NK-TICAs and we will describe herein their discovery and evaluation.We demonstrate potent, selective binding of our Bicycles to receptor-expressing cells and the capability of the bifunctional molecule to induce NK cell function in vitro. With Bicycle’s novel NK-TICA™ compound, we demonstrate the engagement of NK cells, the specific activation and function of NK cells, and enhanced tumor cytotoxicity in a tumor target- and dose-dependent manner.In conclusion, NK-TICAs drive NK cell-mediated tumor cell killing and cytokine production in vitro and as such have the potential to catalyze the development of durable anti-tumor immunity in tumor types not well served by current therapies. We hypothesize that utilization of Bicycle NK-TICA™ as a multifunctional immune cell engager will promote the modulation of NK cells, as well as the infiltration and anti-tumor activity of NK cells in solid tumors. The data presented here provide initial proof of concept for the application of our Bicycle technology to drive NK cell-mediated tumor immunity. Citation Format: Fay J. Dufort, Christopher J. Leitheiser, Gemma Mudd, Julia Kristensson, Alexandra Rezvaya, Katie Gaynor, Sandra Uhlenbroich, Liudvikas Urbonas, Heather Scott, Liuhong Chen, Helen Harrison, Michael Skynner, Kevin McDonnell, Philip E. Brandish, Nicholas Keen. Generation of a Bicycle NK-TICA™, a novel NK cell engaging molecule designed to induce targeted tumor cytotoxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4233.
Abstract LB054: Prometastatic effect of ATX derived from alveolar type II pneumocytes and B16F10 melanoma cells
Authors: Melanie A. Dacheux, Sue Chin Lee, Yoojin Shin, Derek D. Norman, Kuan-Hung Lin, Gabor J. Tigyi
Journal: Cancer Research (2022)

Abstract Although metastasis is the principal cause of cancer-related deaths, the molecular aspects of the role of stromal cells in the establishment of the metastatic niche remain poorly understood. One of the most prevalent sites for cancer metastasis is the lungs. According to recent research, lung stromal cells such as bronchial epithelial cells and resident macrophages secrete autotaxin (ATX), an enzyme with lysophospholipase D activity that promotes cancer progression. In fact, several studies have shown that many cell types in the lung stroma could potentially provide a rich source of ATX in diseases. In the present study, we sought to determine whether ATX derived from alveolar type II epithelial (ATII) pneumocytes could modulate the progression of lung metastasis, which has not been evaluated previously. To accomplish this, we used the B16-F10 syngeneic melanoma model, which readily metastasize to the lungs when injected intravenously. Because B16-F10 cells express high levels of ATX, we used the CRISPR-Cas9 technology to knockout (KO) ATX in B16-F10 cells, eliminating the contribution of tumor-derived ATX in lung metastasis. Next, we used the inducible Cre/lox system (Sftpc-CreERT2/Enpp2fl/fl) to generate conditional KO mice in which ATX is specifically deleted in ATII cells (i.e. Sftpc-KO). Injection of ATX-KO B16-F10 cells into Sftpc-KO or Sftpc-WT control littermates allows us to investigate the specific contribution of ATII-derived ATX in lung metastasis. We found that targeted KO of ATX in ATII cells significantly reduced the metastatic burden of ATX-KO B16-F10 cells by 30% compared to Sftpc-WT mice (unpaired t-test, p=0.0283), suggesting that ATX derived from ATII cells could affect the metastatic progression. We detected upregulated levels of cytokines such as IFNγ (unpaired t-test, p&amp;lt;0.0001) and TNFα (unpaired t-test, p=0.0003), which could favor the increase in infiltrating CD8+-T cells observed in the tumor regions of Sftpc-KO mice. Taken together, our results highlight the contribution of host ATII cells as a stromal source of ATX in the progression of melanoma lung metastasis. Citation Format: Melanie A. Dacheux, Sue Chin Lee, Yoojin Shin, Derek D. Norman, Kuan-Hung Lin, Gabor J. Tigyi. Prometastatic effect of ATX derived from alveolar type II pneumocytes and B16F10 melanoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB054.
Abstract 509: Tumor inflammation signature (TIS) in residual disease is associated with survival in breast cancer patients with high risk of recurrence
Authors: Marco Galvez-Nino, Miluska Castillo, Luis Bernabe, Nancy Suarez, Joselyn Sanchez, Katia Roque, Silvia Neciosup, Henry Gomez, Carlos Castaneda
Journal: Cancer Research (2022)

Abstract Background: The assessment of tumor inflammation signature (TIS) quantifies the adaptive immune response in the tumor microenvironment and is emerging as a predictor of clinical benefit in breast cancer. In this study we evaluated the ability of TIS to be a prognostic biomarker of survival benefit in patients with moderated and high residual disease after neoadjuvant chemotherapy (NAC) in breast cancer patients and its correlation with residual TILS after NAC. Methods: We analyzed 46 samples of residual disease of breast cancer patients who received NAC and were under surgery between 2013 - 2018, with high risk of recurrence defined as Residual Cancer Burden (RCB) group II and III. TIS signature was evaluated using the Research Use Only version of 18-gen signature algorithm. Median of TIS score was 5.88, TIS score were categorized in four groups by quartiles and defined as low TIS score (lower quartile, score ≤ 4.82) and high TIS score (score &amp;gt; 4.82). In addition, we quantified the percentage of stromal TILS in residual disease, categorizing level of TILS in high and low level using median (20%) as a cut-off. Survival analysis was performed with Kaplan-Meier method and the associations with Cox regression model. Correlation between TIS and TILS was performed whit Pearson coefficient. Clinical data was collected of medical records. Results: The median age at diagnosis was 50 years (26y - 78y), 65.2% of patients were Luminal B subtype, 63% were clinical stage IIIB, 26.2% were RCB II and 73.9% RCB III. No correlation between TIS score and percentage of stromal TILS was founded (p = 0.264). After median follow-up of 60 months, estimated median PFS for high TIS score was 71.7 vs 18.2 months for low score (HR = 0.28, 95% CI [0.13-0.64], p = 0.002), and estimated median OS for high TIS score was non-reached vs 40.9 months for low score (HR = 0.28, 95% CI [0.11-0.68], p = 0.005). Did not found differences in PFS (p = 0.408) and OS (p = 0.773) by level of TILS. Conclusions: High TIS score in moderated/high residual disease after neoadjuvant chemotherapy is associated with survival benefit expressed in prolonged PFS and OS. Level of TILS in residual disease did not show differences in survival and its percentage did not have correlation with TIS score. Funding: FONDECYT-198-2015/280-INNOVATEPERU-EC-2017. Citation Format: Marco Galvez-Nino, Miluska Castillo, Luis Bernabe, Nancy Suarez, Joselyn Sanchez, Katia Roque, Silvia Neciosup, Henry Gomez, Carlos Castaneda. Tumor inflammation signature (TIS) in residual disease is associated with survival in breast cancer patients with high risk of recurrence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 509.
Developing the American College of Surgeons Quality Improvement Framework to Evaluate Local Surgical Improvement Efforts
Authors: Clifford Y. Ko, Tejen Shah, Heidi Nelson, Avery B. Nathens
Journal: JAMA Surgery (2022)

The American College of Surgeons (ACS) Quality Programs collect more than 3500 improvement efforts annually.These efforts are usually local (ie, occurring within a hospital) or small scale (ie, low resourced, low funded, or unfunded) 1 and routinely conducted by frontline clinicians and clinical teams.We tried to identify an appropriate and adequate framework to evaluate these improvement efforts; however, no single framework for small-scale, clinician-led improvement efforts exists.Current available frameworks focus on investigative or research-based efforts, efforts led by improvement specialists, or large-scale (ie, resourced, funded) improvements.Herein we describe the development of the ACS Quality Improvement Framework, whose function is to evaluate smallscale surgical improvement efforts.
Abstract 1150: Pharmacokinetics and pharmacogenetics of liposomal cytarabine in AML patients treated with CPX-351
Authors: Melanie Donnette, Mourad Hamimed, Joseph Ciccolini, Regis Costello, Laure Delassus, Geoffroy Venton, Raphaelle Fanciullino
Journal: Cancer Research (2022)

Abstract CPX-351 is a liposomal form encapsulating cytarabine and daunorubicin for treating Acute Myeloid Leukemia (AML) patients. Cytidine Deaminase (CDA) catabolizes free cytarabine in the liver, but to what extent it could affect as well the pharmacokinetics of liposomal cytarabine is yet to be investigated. Here we have studied the pharmacokinetics (PK) of released, liposomal and total cytarabine using a population-modeling approach in adult AML patients treated with CPX-351. Impact of CDA status (i.e., Poor Metabolizer (PM) vs. Extensive Metabolizer (EM)) on cytarabine exposure levels (AUC, trough levels, Cmax) and PK parameters were analyzed. All patients showed febrile neutropenia and one toxic-death was observed. Overall response rate was 75%. The ratio free:total cytarabine monitored in our patients was higher than expected (i.e., 47%). Inter-individual variability on pharmacokinetics parameters and subsequent exposure levels was &amp;gt;60%. A trend towards severe toxicities was observed in patients with higher exposure of cytarabine. Results showed that liposomal CPX-351 led to sustained exposure with reduced clearance (Cl = 0.16 L/h) and prolonged half-life (T1/2 = 28 h). Of note, liposomes were observed transiently in bone marrow on D15, with cytarabine levels 2.3-time higher than in plasma. Sequencing CDA gene was not contributive and CDA status was primarily evaluated upon phenotyping patients. PM status was found in 77% of the patients with a marked impact on cytarabine PK parameters, i.e., PM patients had higher exposure than EM patients (AUC: 5536 vs. 1784 ng/mL.h), prolonged half-life (T1/2: 33.9 vs. 13.7 h), and reduced clearance (Cl: 0.12 vs. 0.29 L/h). This pilot study suggests that despite being encapsulated in a liposomal vehicle as CPX-351, cytarabine fate in the body is highly dependent upon CDA activity, suggesting that liver metabolism is only partly skipped by the nanoparticle. Here, CDA status proved to have a major impact on cytarabine PK and possibly safety in AML patients treated with CPX-351. Indeed PM patients displayed higher exposure levels with higher risk for severe non-hematological toxicities. This study suggests that CDA status could be used as a covariate to customize CPX-351 dosing in AML patients. Citation Format: Melanie Donnette, Mourad Hamimed, Joseph Ciccolini, Regis Costello, Laure Delassus, Geoffroy Venton, Raphaelle Fanciullino. Pharmacokinetics and pharmacogenetics of liposomal cytarabine in AML patients treated with CPX-351 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1150.
Abstract 3081: High-speed live cell interferometry captures heterogeneity in bioprinted tumor organoids
Authors: Peyton J. Tebon, Bowen Wang, Alexander L. Markowitz, Graeme Murray, Ardalan Davarifar, Huyen T. Nguyen, Nasrin Tavanaie, Thang L. Nguyen, Paul C. Boutros, Michael A. Teitell, Alice Soragni
Journal: Cancer Research (2022)

Abstract As interest grows in using tumor organoids as models for drug discovery and precision medicine, platforms for the reliable functional testing and analysis of these organoids are needed. Existing functional approaches in precision medicine face difficulties in the creation, scaling, and analysis of physiological tumor organoid models. We present a method for the automated bioprinting of tumor organoids coupled with real-time biomass quantification using high-speed live cell interferometry (HSLCI). This workflow enhances consistency, preserves sample viability, and assesses response to treatment with single-organoid resolution. First, we describe the bioprinting protocol used to achieve the deposition of organoids in uniformly thin three-dimensional layers of Matrigel. Then we show that bioprinting preserves the histological and molecular characteristics of manually seeded organoids. In drug screening experiments, we demonstrate the simultaneous monitoring of thousands of individual organoids and show that HSLCI can rapidly identify drug sensitivity and resistance to treatment. We observe significant heterogeneity in the drug responses of single organoids and discuss the potential implications for use of this pipeline in the clinical setting. Citation Format: Peyton J. Tebon, Bowen Wang, Alexander L. Markowitz, Graeme Murray, Ardalan Davarifar, Huyen T. Nguyen, Nasrin Tavanaie, Thang L. Nguyen, Paul C. Boutros, Michael A. Teitell, Alice Soragni. High-speed live cell interferometry captures heterogeneity in bioprinted tumor organoids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3081.
Epigenomic and transcriptomic analyses define core cell types, genes and targetable mechanisms for kidney disease
Authors: Hongbo Liu, Tomohito Doke, Dong Guo, Xin Sheng, Ziyuan Ma, Joseph Park, Ha My T. Vy, Girish N. Nadkarni, Amin Abedini, Zhen Miao, Matthew Palmer, Benjamin F. Voight, Hongzhe Li, Christopher D. Brown, Marylyn D. Ritchie, Yan Shu, Katalin Susztak
Journal: Nature Genetics (2022)